Device and method for perfusing peritoneal dialyzing fluid

ABSTRACT

An instrument for continuous recirculation of peritoneal dialysate to infuse and drain out the dialysate automatically through catheters implanted in a peritoneal cavity of a human body. The instrument includes a prefilter, a primary filter comprising a semipermeable membrane having a maximum permeable molecule of up to 30,000 dalton, a pump for lowering the outside pressure of the primary filter relative to the inside pressure, a secondary filter having a semipermeable membrane having a maximum permeable molecule of 5,000 dalton, a pump for raising the pressure of a supplemental liquor line relative to the inside of a secondary filter line, and a method of recirculating dialysate using the above-mentioned instrument. The recirculation instrument permits the reuse of protein which is permeated out from a patient&#39;s body, as an osmotic agent in peritoneal dialysate, in order to maintain a disinfected recirculating line, and to improve an ultrafiltration rate and clearance of uremic toxin.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a peritoneal dialysis instrument forimproving dialysis efficacy in removing excess liquid and uremic toxinby maintaining polymer osmotic agents in place of glucose in arecirculation line without requiring outside contact for the therapy ofchronicle renal failure disease.

2. Description of the Related Art

Peritoneal dialysis has been applied as an effective therapy for renalfailure patients. The dialysis is performed so that dialysate is infusedinto the peritoneal cavity from the dialysate bag through a catheter,which is implanted in the patient's peritoneal cavity, and the dialysateis stored in the cavity for a certain time. Then, the dialysate isdrained out through the same catheter. This procedure is repeated a fewtimes a day.

This dialysis has a few advantages over hemodialysis from aphysiological point of view, as it purifies blood continuously throughthe patients' peritoneum, while hemodialysis uses artificial membranes.Also, peritoneal dialysis enables the patients to participate in socialactivity, and as a result, the dialysis has been widely applied.

In hemodialysis, ultrafiltration is achieved by raising the pressure ofthe blood line over that of the dialysate line. However, the same methodcan not be applied to peritoneal dialysis. As a result, an osmotic agentis added into the dialysate so as to raise the osmotic pressure of thedialysate over that of plasma, and the dialysate is infused into theperitoneal cavity so as to contact it to the peritoneum for removingexcess liquid from the patient's body. For this purpose, glucose hasbeen used as an osmotic agent. However, adverse effects such as thedisfunctioning of the, peritoneum due to the absorption of such a largequantity of the osmotic agent into the patient body are now recognizedas a serious problem.

For solving the aforementioned problem, the inventor of the presentinvention has proposed an instrument and a method by which serumprotein, such as albumin, globulin and the like which are permeated outthrough peritoneum into the dialysate, is recovered and refined, and isthen concentrated and reused with dialysate as the most physiologicalsubstitutes of glucose.

In these proposed processes, the following were disclosed:

(A) A method to dissolve the recovered and refined protein in dialysateafter which low molecular weight uremic toxin substances not higher than30,000 daltons are removed by the repeated concentration/dilutionprocedures with a semipermeable membrane, and to reuse it as asubstitute of glucose. (Japanese Laid Open Patent Application Hei9-327511)

(B) A method to keep the abovementioned device and the componentsdisinfected. (Japanese Laid Open Patent Application Hei 10-85324)

(C) A method to separate the malignant solute in the solvent and refinethe protein by acidifying the protein and then de-acidifying it throughwater dialysis so as to deposit it at iso-electric pH (Japanese LaidOpen Patent Application Hei 9-302388)

Also, for carrying out the invention (C), it was disclosed that thedevice comprises the followings:

(D) An inflow line having a filter whose maximum pore size is 100-300nanometers for preventing bacteria invasion into the peritoneal cavity;and

(E) A two step prefilter having a pore size between 5 and 200 microns toremove blood cells, peritoneum mesothelial cells, fibrin and the likesuspended in the effluent when it is drained out from peritoneal cavity.

A few attempts have been reported to utilize serum protein in ascites(Hwang, E. R., Richard, D. O. Sherman, A. et al., Dialytic AscitesUltra-filtration in Refractory Ascites, Am. J. Gastroenteral, 77(9):652-654, 1982, for example)

However, they did not refer to removing uremic toxin, because theirtarget was not a renal failure patient.

Also, a method to add a peritoneum protecting component of a molecularweight of not higher than 3,000 daltons recovered from peritonealdialysis effluent into dialysate (Japanese Laid Open Patent ApplicationHei 8-337590). However the recovery and reuse of the component of themolecular weight higher than 3,000 daltons is not suggested.

When plasma protein that is permeated out of the patient body is reusedas an osmotic agent in place of glucose, the following conditions needto be satisfied:

(I) To minimize the contact with atmosphere and foreign matters so as tonot denature the protein;

(II) To minimize plugging the semi-permeable membrane on therecirculation line, and to decrease the frequency of exchange; and

(III) To completely prevent the invasion of pathogenic bacteria andendotoxin.

For the solution of the aforementioned (I) problem, it may be suggestedthat a filter is set at the exit of the catheter, or, as a furtherperfect protection, a hollow fiber type semi-permeable membrane is setin a peritoneal cavity in order to keep the polymer in the peritonealcavity. However, in those cases, complicated preventive means arerequired to avoid plugging of the membrane, and the exchange of thefilter requires skillful care.

SUMMARY OF THE INVENTION

The present invention has developed a practical method and an instrumentfor solving the aforementioned problems, by the combination of eitherone of the following technologies:

[I] The drained dialysate is warmed up to a preset temperature, and thenit is filtered through a prefilter for removing foreign materials so asto prevent the plugging of the filter.

[II] A semi-permeable membrane (having a cut-off point of up to 30,000dalton) filter is used for removing uremic toxin of low molecular weightand of middle molecular weight.

[III] A supplemental electrolyte solution is supplied through asemi-permeable membrane filter (having a cut-off point of up to 5,000dalton) for preventing the infection and invasion of endotoxin.

Also, the present inventor has found that by the use of the device,dialysate may be drained out of the peritoneal cavity and may berecirculated in a closed line. In addition, a portion of the dialysatemay be filtered out through a semi-permeable membrane to removemalignant component, and then, a fresh dialysate may be supplementedthrough a semipermeable membrane and returned automatically into theperitoneal cavity.

Briefly, the present invention relates to an instrument-that comprises(a) a prefilter, (b) a first filter that comprises a semi-permeablemembrane having a maximum permeable molecule of up to 30,000 dalton, (c)a pump to lower the outside pressure of the first filter (b) relative tothe inside pressure, (d) a second filter that comprises a semi-permeablemembrane having a maximum permeable molecule of 5,000 dalton, (e) and apump to raise the pressure of a supplemental liquor line relative to theinside line of the second filter.

Also, the present invention relates to a method characterized in thatdialysate is drained out of the peritoneal cavity and recirculated in aclosed line, and a portion of the dialysate is filtered out through asemi-permeable membrane. Then, an equivalent volume of fresh dialysateis supplemented through a semi-permeable membrane having a maximumpermeable molecule of 5,000 dalton and is then returned into theperitoneal cavity.

As a favorable embodiment for carrying out the present invention, thefollowing technologies may be adapted:

(1) A bacteria-free filter (having a maximum pore size of 100-300nanometers) is set up on the peritoneal cavity side of the inflow line'sjoint.

(2) Dialysate in the peritoneal cavity is recirculated through aperfectly closed and continuously connected and previously disinfectedline for keeping the protein not denatured in the automatic dialysaterecirculation instrument.

(3) A reverse flow prevention valve (anti-reverse flow valve) is set upon the withdrawn line.

(4) A closed chamber, of which the inside can not directly be contactedby fingers, is set up for disconnection and connection procedure byremote operation from outside, after the infusion of dialysate for thedaytime cycle before getting up in the morning.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a Peritoneal Dialysate Recirculation Circuit in anighttime state where the peritoneal dialysate recirculation instrumentis connected with the patient's outflow and inflow catheters,respectively, and the dialysate is recirculated.

FIG. 1(a) is an enlargement of the structure of the primary filter andthe secondary filter of FIG. 1 and illustrates the flow of the dialysateand a supplemental solution therethrough.

FIG. 2 illustrates an exchanging method of an outflow line joint and aninflow line joint for:

(a) a disconnecting operation of the joint, which has been directlyconnected in the daytime (FIG. 3), and a rotation operation of theparts; and

(b) a rotating operation of the disconnected part so as to face the partof peritoneal cavity side and the part of recirculation instrument side,and a connecting operation of the parts so as to make ready fornighttime recirculation (FIG. 1).

FIG. 3 illustrates an O-shaped circuit of the catheter at anextracorporeal side (during a daytime state when the patient leaves andis away from the recirculation instrument for daily life) and hollowfibers in the peritoneal cavity.

EXPLANATION OF THE REFERENCE NUMERALS

1. Peritoneal Cavity

2. Outflow Catheter

3. Joint

4. Anti-Reverse Flow Valve

5. Outflow Line Joint

5 a. Patient Peritoneal Cavity Side Terminal of Outflow Line Joint

5 b. Recirculation Instrument Side Terminal of Outflow Line Joint

6. Heater

7. Prefilter

8. Bacteria-free Filter

9. Pump

10. Primary Filter

11. Secondary Filter

12. Suction Pump

13. Feeding Pump

14. Supplemental Solution Vessel

15. Pump

16. Pump

17 a. Container

17 b. Reservoir of Osmotic Agents

18. Warmer

19. Inflow Line Joint

19 a. Patient Peritoneal Cavity Side Terminal of Inflow Line Joint

19 b. Recirculation Instrument Side Terminal of Inflow Line Joint

20. Bacteria-free Filter

21. Joint

22. Inflow Catheter

23. Reverse Osmosis Membrane Water

24. Inlet Valve of Chemicals

25. Loupe-shape Hollow Fibers

26. Isolated Case

DETAILED DESCRIPTION OF THE INVENTION

The present invention will be explained with reference to FIG. 1.

FIG. 1 illustrates an outflow catheter 2 and an inflow catheter 22 in aperitoneal cavity 1.

It happens to be observed often that when liquor is recirculated from aninflow entrance to an outflow exit at a consistent rate, a localizedflow, a so-called channeling, is formed in the peritoneal cavity; then,a portion of the liquor tends to stay at “dead spaces”. For solving thisproblem, a certain number of loop-shaped porous hollow fibers 25 arefixed at the end of the inflow catheter so that the dialysate may flowthroughout the cavity as illustrated in FIG. 3. Instead of an outflowcatheter 2, an outer lumen of a concentric double lumen catheter mayalternatively be used.

Outflow catheter 2 comprises joint 3, anti-reverse flow valve 4, andoutflow joint 5, and the flow catheter is connected with heater 6 andprefilter 7 in series.

Outflow joint 5 comprises peritoneal side part 5 a and instrument sidepart 5 b, as illustrated in FIG. 3. During recirculation time, whichoccurs at night, the parts 5 a and 5 b are connected together. The joint5 has the structure of male/female parts, which are directly adaptableto each counterpart of inflow joint 19, as is discussed further below.During the daytime, which is when dialysate is not recirculated but isstored in the peritoneal cavity, the joint part 5 a is connected withthe joint part 19 a, and the joint part 5 b is connected with the jointpart 19 b, thereby forming the circuit illustrated in FIG. 3.

The dialysis effluent that is drained out of the patient's peritonealcavity contains peritoneum mesothelium cells, leucocyte cells, depositedfibrin, and the like. These foreign particles may be separated from thefiltrate with prefilter 7.

Fibrinogen in the dialysate effluent tends to be deposited out as fibrinafter prefiltration, and it plugs the filter. This has often beenexperienced when plasma and humor is filtered. For preventing theplugging problems, it is desirable to warm up the effluent up to 55-60°C. by means of a heater before prefiltration.

After the dialysate is passed through a bacteria-free filter 8, it isflown by pump 9 to the first filter 10 and then to the second filter 11.The first filter has a semi-permeable membrane of a maximum permeablemolecule of up to 30,000 dalton, greater than that of 2-microglobulin,for example. By filtering out a portion of the dialysate through thisfilter, middle molecule malignant components, such as a 2-microglobulinof the molecular weight of 11,800 daltons, may be removed.

After filtering through the first filter, the partially filtereddialysate is supplemented with a supplemental electrolyte solution. Thesupplemental solution is added through the second filter whosesemipermeable membrane does not pass endotoxin. The second filter has asemipermeable membrane of a maximum permeable molecule of up to 5,000dalton so that it can prevent invasion of bacteria and endotoxin.

Endotoxins are lipopolysaccharides, of which the largest ones have amolecular weight of a few hundred thousand dalton. The smallestlipopolyssaccharides have a molecular weight of 6,000-8,000 dalton. Onthe other hand, supplemental chemicals and additives are lightermolecules, such as 1,000 dalton, so that they may pass through thissemipermeable membrane of the second filter 11.

Due to the reduced pressure in the outside of the first filter 10 bysuction pump 12, dialysate in the first filter 10 is suctioned out. Thesupplement solution in the second filter is pressed by feeding pump 13to feed in through the second filter 11. The filtration in both filtersis accelerated by these pumps 12 and 13.

FIG. 1(a) illustrates an enlargement of the structure of the primaryfilter 10 and the secondary filter 11, and the flow of the dialysate andthe supplemental solution. As shown in FIG. 1(a), the primary filter 10and the secondary filter 11 each comprise a number of hollow fibers. Thesections labeled as Section A are inside the hollow fibers which leadthe dialysate rightward to the secondary filter 11. The sections labeledas Section B are outside of the primary filter 10 and lead the suctionedfiltrate upward to be discarded by the suction pump 12. The individualsections of Section B appear to be isolated, but in fact, they are in acontinuous space leading to the suction pump 12. In the suctionedfiltrate, middle molecules of less than 30,000 dalton are therebyremoved as indicated by the upward arrow from primary filter 10 to thesuction pump 12.

The supplemental solution is stored in a supplemental solution vessel14, and it is sent to the second filter by feeding pump 13 as indicatedby the downward arrow from the supplemental solution vessel 14 and thesupplemental liquor line (sections labeled as section C of the secondaryfilter 11) into the secondary filter line (sections D on the inside ofthe hollow fibers of the secondary filter 11). Amino acids, fatty acids,glucose, peptides or any mixture thereof are added into the supplementalsolution through a line which is connected with a valve 24 that isequipped in the supplemental solution vessel 14.

The above-mentioned supplemental solution may be:

(a) a commercially available infusion solution or peritoneal dialysatewhich is sterilized and packed in a supplemental solution vessel 14, or

(b) a hemodialysis concentrate or dry chemicals for hemodialysis, whichis diluted or dissolved with, reverse osmosis water.

After partial filtration in the first filter 10 and supplementation atthe second filter 11 the dialysate is flown by pump 16 through a warmer18, where it is warmed up to a standard corporeal temperature. Then, thedialysate is infuised through inflow joint 19, bacteria-free filter 20,and joint 21 so as to pass into peritoneal cavity 1.

On the by-pass line 15-17 a-9, a container 17 a is set up, where aportion of polymer components, which is stored in the peritoneal cavityduring the daytime, may be stored. The solution can be circulatedthrough the line by pump 15 so as to repeat the concentration/dilutionprocedures. A cooling or freezing unit may be equipped for the container17 a.

One of the present invention's aims is the reuse of recovered plasmaprotein permeated from a patient's body through peritoneum into thedialysate.

However, in the case where the recovered protein is not enough toachieve sufficient ultrafiltration, other osmotic agents may besupplemented. Such supplemental agents may be high or low molecularweight substances.

High molecular weight substances maybe oligosaccharides, and lowmolecular weight substances may be glucose or amino acids. Even whensubstances whose daily dose is restricted are used, usage is within atolerable quantity, and those osmotic agents may be used so that therequired osmotic pressure can be obtained. Low molecular weight agentsare added from a supplemental reservoir 14, and high molecular weightagents are supplied from an osmotic agent reservoir 17 b into thecontainer 17 a, where the additives are mixed with the dialysate.

The recirculation instrument is connected with peritoneal catheters atnight so as to automatically achieve peritoneal dialysate recirculation.However, in the daytime, joint 5 and joint 19 are disconnected from therecirculation instrument and form a daytime circuit as illustrated inFIG. 3. For such a disconnection and connection operation, each jointcomprises a respective part a and part b as illustrated in FIG. 2. Thatis, joint 5 consists of parts 5 a (male) and 5 b (female), and joint 19consists of parts 19 a (female) and 19 b (male). When parts 5 a and 5 bare disconnected from each other and parts 19 a and 19 b aredisconnected from each other, parts 5 a and 19 a can be connected andparts 5 b and 19 b can be connected as illustrated in FIG. 3. Accordingto the present invention, outflow joint 5 and inflow joint 19 are set upadjacently in an isolated case 26 and manipulated from outside of thecase to be isolated and free from human contact.

By use of the recirculation instrument according to the presentinvention, extraperitoneal recirculation procedures may be achievedcontinuously and automatically in the following way. First, before thepatient begins sleeping, parts 5 a and 19 a and parts 5 b and 19 b,which have been respectively connected in the isolated case 26 duringthe daytime, are disconnected. Then, each part is rotated by 90 degreesto the direction along the arrows as illustrated in FIG. 2. Then, parts5 a and 5 b are connected, and parts 19 a and 19 b are connected to forma recirculating circuit as illustrated in FIG. 1.

When the circuit line is set up, recirculation is started. Afterconcentrating the drained dialysate and removing uremic toxin in thefirst filter, a portion of the concentrate is stored in the container 17a.

The remaining concentrate is added to a fresh electrolyte solutionthrough the second filter 11, and then is infused into the peritonealcavity. If needed, concentrating/diluting procedures are repeated a fewtimes through a circulation circuit (16-17 a-9). In some cases, anelectrolyte solution, such as amino acids, glucose, fatty acids, orpeptides, etc., is added.

Not only sodium caprilate and N-acetyltryptophan are added asstabilizers to prevent the recycled protein from becoming denatured, butacids, alkali, and anti-oxidants, such as, glutathione, vitamin C,vitamin E and reductants, are also added to the electrolyte solution soas to release urea, bilirubin, and S—S bonded chemicals that areattached to cysteine, 34^(th) amino acid from N-terminal of albumin. Bymaking albumin as active as those of healthy persons by theabovementioned way before infusing it into the peritoneal cavity, it maythereby improve the therapy effect.

Thus, the dialysate in the peritoneal cavity is consistently drainedout, and is substituted partly with a fresh electrolyte solution by theway of recirculation at night when the patient sleeps.

Before getting up in the morning, all or almost all of the dialysate inthe peritoneal cavity is drained out, and the drain is repeatedlyconcentrated and diluted. Then, the aforementioned chemicals are addedand infused into the peritoneal cavity. The joints 5 and 19 aredisconnected to form a circuit as illustrated in FIG. 3 by directlyconnecting the corresponding part of joint 5 with the corresponding partof joint 19. Briefly, as in FIG. 3, on the catheter side, an “O” shapedcircuit is formed. On the catheter side, part 19 a is connected to abacteria-free filter entrance 20 on the inflow line, and part 5 a isconnected to an anti- reverse flow-valve exit 4 on the outflow line. Onthe recirculation instrument side, the counter parts 5 b and 19 b areconnected.

The above-mentioned operation can be manipulated in a separate case soas to prevent human contact, and through which a continuousrecirculation of the dialysate can be performed.

By use of the instrument according to the present invention, continuousrecirculation can be achieved simultaneous to a partial substitution ofthe dialysate.

By the instrument according to the present invention, safely reusing thepermeated out protein into the peritoneal dialysate, and continuousrecirculation of the dialysate can be achieved in the simplest way.Briefly, every day, dialysate is drained out and infused through asemipermeable membrane, and solution flows through a completely closedcircuit line so as to minimize the risk of infection.

By the instrument according to the present invention, continuousrecirculation of the dialysate can be achieved simultaneous to a partialsubstitution. As a result, continuous draining of the dialysate out ofthe peritoneal cavity and partial substitution of the dialysate withfresh electrolyte solution can be achieved during the nighttime when thepatient sleeps. After getting up in the morning, the patient can bedisconnected from the instrument and thereafter enjoy a daily life inthe daytime without being connected to an external instrument.

It has been said that increasing the number of dialysis cycles per dayis effective for improving the dialysance of peritoneal dialysis.However, too many cycles of peritoneal dialysis increases the vacancytime of a peritoneal cavity. To solve this problem, the use of tidaltype recirculation has been proposed. However, tidal type recirculationleaves a portion of liquid in the peritoneal cavity, and it can notimprove the dialysance significantly.

The present invention, in contrast, can improve the dialysance, as thedialysate recirculates without a vacancy time in the peritoneal cavity.Another recirculating method in which the dialysate is refined byextraperitoneal dialysis by use of an artificial dialyser andextracoporial dialysate can improve the dialysance, but thisrecirculating method requires a large volume of dialysate. The presentinvention provides a much more economical dialysis due to a partialsubstitution of recirculated dialysate. This advantage is also valid inthe case where no polymer component is contained and recycled.

Instead of requiring large volumes of dialysate to be delivered, on sitepreparation of dialysate by diluting the dialysate concentrate or bydissolving dry chemicals is very effective for reducing the cost oftherapy. The water preparation device for the dissolution and dilutionby reverse osmosis membrane may be equipped in the instrument accordingto the present invention so as to provide a safe and low cost dialysate.

Infection can be prevented by the use of a previously connected, packedand sterilized extracorporeal recirculation line. Also, the infectionrate at a periodical exchange can be significantly reduced by having theoutflow and inflow connection parts fixed adjacent to one another in aclosed case as illustrated in FIG. 2, and the connection parts can bedisconnected and exchanged by outside manipulation free from contact ofthe atmosphere and other foreign, e.g. human, contact.

By using the above-described method and instrument, the presentinvention enables (I) minimizing contact with the atmosphere and otherforeign matters such as human contact, (II) minimizing the plugging ofthe semi-permeable membrane on the recirculation line, and (III)perfectly preventing the invasion of bacterial and endotoxin fromexternal sources.

What is claimed is:
 1. An instrument for continuous recirculation ofperitoneal dialysate to infuse and drain out the dialysate automaticallythrough catheters implanted in a peritoneal cavity of a human body, saidinstrument comprising: a prefilter; a primary filter located downstreamof said prefilter, said primary filter being operable to filter out aportion of the dialysate, and said primary filter comprising asemipermeable membrane having a maximum permeable molecule of up to30,000 dalton; a suction pump operable to lower an outside pressure ofsaid primary filter relative to an inside pressure of said primaryfilter; a feeding pump operable to supply a fresh dialysate; and asecondary filter located downstream of said feeding pump, said secondaryfilter being operable to filter out a portion of the fresh dialysate,and said secondary filter comprising a semipermeable membrane having amaximum permeable molecule of up to 5,000 dalton.
 2. The instrument forcontinuous recirculation of peritoneal dialysate according to claim 1,wherein a supplemental liquor line provides communication between saidfeeding pump and said secondary filter.
 3. The instrument for continuousrecirculation of peritoneal dialysate according to claim 2, wherein saidfeeding pump supplies the fresh dialysate to said secondary filterthrough the supplemental liquor line, said feeding pump being furtheroperable to raise the pressure of the supplemental liquor line relativeto an inside pressure of said secondary filter.
 4. The instrument forcontinuous recirculation of peritoneal dialysate according to claim 1,wherein the instrument is equipped with a dialysate recirculation linethat is replaceable, made of flexible material, prefabricated as acontinuous line from an outflow terminal to an inflow terminal, andsterilized.
 5. The instrument for continuous recirculation of peritonealdialysate according to claim 4, further comprising an outflow joint andan inflow joint which can be directly connectable to each other, and inan isolated case the outflow and inflow joints can be fixed adjacent toeach other so that terminals of a recirculation instrument side andterminals of a patient peritoneal cavity side may be disconnected andconnected by remote handling free from human contact.
 6. The instrumentfor continuous recirculation of peritoneal dialysate according to claim1, further comprising an outflow joint and an inflow joint which can bedirectly connectable to each other, and in an isolated case the outflowand inflow joints can be fixed adjacent to each other so that terminalsof a recirculation instrument side and terminals of a patient peritonealcavity side may be disconnected and connected by remote handling freefrom human contact.
 7. The instrument for continuous recirculation ofperitoneal dialysate according to claim 1, wherein said prefilter, whichis located upstream of said primary filter, is operable to prevent saidprimary filter from becoming plugged by cells and fibrin in thedialysate withdrawn from the peritoneal cavity.